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Anti-angiogenic therapy in breast cancer
Biomedicine & Pharmacotherapy 57 (2003) 463–470 www.elsevier.com/locate/biopha
Dossier: Breast cancers
Anti-angiogenic therapy in breast cancer Mohammad Atiqur Rahman, Masakazu Toi * Breast Cancer Research Program, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan Received 10 September 2003
Abstract Breast cancer is a worldwide epidemic among women, and one of the most rapidly increasing cancers. Not only the incidence rate but also the death rate is increasing. Despite enthusiastic efforts in early diagnosis, aggressive surgical treatment and application of additional non-operative modalities, its prognosis is still dismal. This emphasizes the necessity to develop new measures and strategies for its prevention. The understanding of the biology of angiogenesis is improving rapidly, offering the hope for more specific vascular targeting of tumor neovasculature. Anti-angiogenic therapy is a promising, relatively new form of cancer treatment using drugs called angiogenesis inhibitors that specifically inhibit new blood vessel growth. Extensive studies conducted over the past few years have recognized that overexpression of COX-2, VEGF in the cancer might be the leading factors, can induce angiogenesis via induction of multiple pro-angiogenic regulators. Breast tumor growth and metastasization are both hormone-sensitive and angiogenesis-dependent. A single angiogenic inhibitor is not capable to inhibit angiogenesis. Therefore, we should select a combination of angiogenesis inhibitors targeting COX-2, VEGF, and bFGF pathway. This article reviews the background and implementation of the current use of angiogenesis inhibitors and discusses the likely therapeutic roles in the early and advanced breast cancer together with its potential for chemoprevention. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: COX-2; VEGF; Breast cancer; Angiogenesis; Cancer prevention
1. Introduction Angiogenesis, formation of new capillaries from preexisting blood vessels, not only is important in physiological processes but also contributes in a variety of pathological processes, and various inflammatory disorders [1]. In particular, for the localization and expansion of a small solid tumor into neoplasm, angiogenesis is the vital process, and making cancer a clinically relevant target for antiangiogenesis therapy [2]. Tumor angiogenesis is a complex mechanism consisting of multi-step events including secretion or activation of angiogenic factors by tumor cells, activation of proteolytic enzymes, and proliferation, migration, and differentiation of endothelial cells [3]. Anti-angiogenic therapy represents a new promising therapeutic modality in solid tumors. It may also be used as a maintenance therapy to prevent the metastasis or recurrence. Current approaches to target angiogenesis rely on inhibiting growth factors that stimulate vascular endothelial cells or blocking their receptors to breast cancer. * Corresponding author. E-mail address: [email protected] (M. Toi). © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. doi:10.1016/j.biopha.2003.09.009
Breast cancer is the most common primary cancer with poor prognosis. Although localized breast cancer can be cured by surgery, breast cancer has a high mortality rate primarily due to frequent metastasis while the primary tumor is undetected. Breast cancer development is a complex process associated with an accumulation of genetic and epigenetic changes that run through the steps of initiation, promotion and progression. However, the precise implication of etiological factors in the genetic pathway of breast cancer development has not yet been fully understood. Accordingly, understanding the mechanisms that control breast cancer growth behavior is of great importance in order to prevent and more efficiently control its genesis. Beyond any doubt this fundamental understanding of tumor biological and molecular behavior can be proved to be of high validity in the evolution of effective therapy. Cyclooxygenase (COX), constitutively expressed COX-1 and inducible COX-2, which has recently been categorized as an immediate-early (IE) response gene, are the rate-limiting enzymes catalyzing the production of prostanoids (prostaglandins (PGs) and thromboxanes) from arachidonic acid. As COX-2 expression is minimal in different, normal and human tissues, COX-2
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overexpression in cancer tissues has been implicated as a promoting factor in carcinogenesis, whilst genetic deletion or pharmacological inhibition of COX-2 suppresses tumorigenesis [4,5]. Additionally, the localization of factors (NFjB, selective promoter factor (SP-1), CCAAT enhancerbinding proteins) well connected with breast cancer progression in the promoter region of COX-2 [6] emphasizes the central role that COX-2 can play in breast cancer biology. 2. Natural history of angiogenesis in breast cancer Both primary and metastasis tumors in the breast are dependent on angiogenesis and primary malignant breast tumors are among those human neoplasms that exhibit the greatest angiogenic activity. Recently, the significance of tumor angiogenesis as a prognostic indicator has been documented in various kinds of human tumors [7,8]. The development of immunohistochemical techniques using monoclonal antibodies against endothelial mitogens like factor VIII-related antigen (RA) allowed the semiquantitative analysis of microvessel proliferation in tumor tissues [9]. Using this evaluation method, Weidner et al. [10] first reported that tumor angiogenesis is an independent prognostic indicator in primary breast cancer. Furthermore, Hork et al. [11] confirmed its value by an immunocytochemical method using another monoclonal antibody for platelet/endothelial cell adhesion molecule, CD-31. We also found that microvessel density (MVD) is a potent prognostic indicator in primary breast cancer [12]. Recently, Costa et al. [13] showed a significant correlation between COX-2 expression and MVD in human breast cancer. COX-2 can be induced by a variety of factors including tumor promoters, cytokines, growth factors and hypoxia. Recent findings have demonstrated that activation of the mitogenic-activated protein kinase (MAPK) and protein kinase B signaling pathways (Akt/PKB signaling pathways) are important in both the transcriptional and posttranscriptional regulation of COX-2 expression [14]. HuR protein, an ubiquitously expressed member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, has been identified as a trans-acting factor involved in mRNA-stabilization and has been characterized as an important mRNA-stability factor [15]. Recent studies suggest that HuR, by binding to the COX-2 AU-rich element prolongs the half-life of COX-2 mRNA and ultimately leads to the overexpression of COX-2 in colon carcinoma cells [16]. A similar mechanism responsible for the COX-2 overexpression in breast cancer cells may also occur, as a high expression of HuR has been observed in breast cancer cell lines [17]. Thus, future studies investigating the relationship between HuR and COX-2 in breast cancer would be of special interest. Vascular endothelial growth factors (VEGF) also referred to as vascular permeability factor (VPF) has been characterized as the most potent regulator of angiogenesis in human carcinogenesis. VEGF exerts its biologic activities through two transmembrane tyrosine kinase receptors: the fms-like
tyrosine kinase receptor (Flt-1, or VEGFR1) and kinase insert domain-containing receptor (KDR or VEGFR2). Recent results suggest that human anti-KDR antibodies may have potential application in the treatment of cancer and other diseases in which pathologic angiogenesis occurs [18]. In a recent study, it has been shown that an oral DNA vaccine that selectively targets VEGFR2 is capable of preventing effective angiogenesis and inhibits tumor growth [19], which demonstrated that immunotherapy directed against proliferating endothelial cells could be used to selectively target malignancy [20]. Various therapeutic approaches aimed at inhibiting the function of VEGF are currently under investigation [21]. VEGF-targeting treatments include large molecules such as neutralizing antibodies against VEGF, VEGFRs, the soluble form of VEGFR1 (sVEGFR1), and small molecules such as signal transduction inhibitors. sVEGFR1, an intrinsic inhibitor of VEGF, frequently co-expressed with VEGF in primary breast cancer tissues. The balance between sVEGFR1 and VEGF levels in breast cancer tissues provided more statistically significant prognostic value than VEGF alone, supported an anti-angiogenesis treatment including anti-VEGF therapy [22]. Recombinant humanized monoclonal antibodies to VEGF (rhuMab VEGF) are now being investigated in phase II/III clinical trials. Results from phase I study show that rhuMab VEGF was well tolerated in various doses, and pharmacokinetic studies indicated that the antibody had a similar half-life to other humanized antibodies. According to a recent presentation at 2003 American Society of Clinical Oncology (ASCO) meeting, it was documented that an addition of rhuMab VEGF to conventional standard treatment improved the survival outcomes in colo-rectal cancer magnificently. In metastatic breast cancer, it was also shown that rhuMab VEGF plus capecitabine achieved a significantly higher tumor response rate as compared with capecitabine alone in the third-line treatment, despite the survival advantage not being demonstrated. Experimentally, monoclonal antibodies against VEGFR1 and VEGFR2 have activities against various types of tumors [23]. In a neuroblastoma model, combination therapy with a monoclonal neutralizing antibody targeting VEGFR2 and vinblastine resulted in full and sustained regression of large established tumors, without an increase in toxic effects or any signs of acquired drug resistance during the treatment period [24]; this approach, therefore, seems promising. Treatment with the soluble form of VEGFR1 has also shown to inhibit VEGF-induced neovascularization, because soluble VEGFR1 can bind to VEGF with high affinity and neutralize its activity effectively. Recently, a new form of VEGF receptor, neuropilin-1, has been identified, which plays an important role in vasculogenesis [25] and is involved in VEGF mediated angiogenesis in vivo [26,27]. Matthies et al. [28] showed that anti-neuropilin exhibited a significant decrease in wound angiogenesis. However, additional studies are needed to explain the mechanism of neuropilin-1 activity in angiogenesis.
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Platelet derived growth factor (PDGF) and its receptor (PDGFR) transduce signals that direct cellular growth, division, and migration. Increased PDGF/PDGFR activity is required for angiogenesis and may be oncogenic. Receptor binding by PDGF is known to activate intracellular tyrosine kinase, leading to autophosphorylation of the cytoplasmic domain of the receptor as well as phosphorylation of other intracellular substrates. PDGF has been identified as a potential autocrine growth factor for sarcoma [29]. Breast carcinomas are known to express PDGF [30]. Recently, it has been shown that Gleevec (tyrosin kinase inhibitor) can exert its inhibitory effect on tumor cells through inhibiting PDGF receptor function in primary non-small cell lung cancer [31]. Gleevec, that has been proven to be effective for clinical cancer patients, represents a new direction in drug design targeting specific tyrosine kinases important for intracellular signal transduction pathway. Fibroblast growth factors (FGF), especially the bFGF are one of the best-characterized and most potent angiogenic factors. Recently, another tyrosin kinase receptor family, TIE-1 and TIE-2 receptors, have been found to be critically involved in angiogenesis. Von Hippel– Lindau (VHL) tumor suppressor gene product has been found to play a critical role in the activation of hypoxia inducible factor-1 alpha (HIF-1a), which might lead to a new understanding for the mechanism of hypoxia-induced neovascularization. Her-2/new may regulate COX-2 production of proinflammatory PGs, both in the ER positive and negative breast cancer, which is known to play a key role in tumor development. Further research is necessary to elucidate the roles of Her-2/new and COX-2 in the development of breast cancer. Angiogenesis is a multistep cascade involving various soluble mediators, and interacts closely with the immune system either directly or indirectly. Particularly, macrophage chemoattractant protein-1 (MCP-1), an important angiogenic factor [32], has been shown to correlate significantly with angiogenesis and TAM accumulation in primary breast cancer [33]. Furthermore, a combined MCP-1 and VEGF status was an independent prognostic indicator, which suggests that the immune-regulating function and angiogenic function of MCP-1 might contribute to the poor prognosis of breast cancer [33]. On the other hand, thymidine phosphorylase (TP) an important angiogenic enzymes, induce new blood vessel formation in many human malignancies. TPoverexpressing tumor cells grow faster and form more angiogenic tumors than do wild-type TP (–) ve tumor cells in nude mice. TP expression was positively associated with MVD and with poor prognosis in gastrointestinal cancer. In an immunohistochemical analysis, we also found that monocytic TP (+) ve breast tumors had a significantly worse prognosis than did monocytic TP (–) ve breast tumors [34]. Although there is no direct evidence of TP as an effective contributor to the angiogenic process, but it is associated with aggressive histological features when co-expressed with VEGF [35]. Recently, it has also been suggested that COX-2 expression was associated with TP expression.
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3. Regulation of angiogenic factor in breast cancer The concept of angiogenic factor was postulated by Folkman’s group two decades ago. In recent years, many new angiogenic factors have been identified and characterized, but still little is known about the relationship between specificity of angiogenic factors and type of tumor. With the emergence of anti-angiogenic therapy as a novel anti-cancer treatment, the value of understanding the mechanism(s) driving the regulation of angiogenic mediators, such as VEGF in breast cancer, has increased. Often produced at high levels by tumor cells, VEGF is a well-known mediator of tumor angiogenesis, which stimulates EC growth and enhances vascular permeability. According to several hypotheses, in human breast cancers COX-2 overexpression is linked to VEGF overexpression and, therefore, tumor angiogenesis [36] and/or PG production (Fig. 1). The hypoxia-induced VEGF up regulation can be mediated by COX-2 [37]. In hypoxic condition, overexpression of COX-2 induces VEGF expression by modulating HIF-1a [38]. It has been shown that PGE2 induce translocation of HIF-1 alpha into the nucleus where it binds with ARNT/HIF-1a and then induce VEGF (Fig. 2). Furthermore, it is well known that PGs can induce tumor angiogenesis in an autocrine and/or paracrine fashion and even more specifically are important growth regulators as they stimulate cellular proliferation in rat and human (e.g. PGE2 and PGE2a) [39]. Although there are only a limited number of studies describing the role of COX-2 in angiogenesis and tumor neovascularization in breast cancer in particular, it seems that it is only a matter of time before the critical role of COX-2 in this high-importance mechanism for tumor growth is established [40]. Tumor vascularity is a strong indicator of its biological aggressiveness in breast cancer especially, as it is significantly correlated with clinical and histological grades of the carcinoma [41]. The protagonistic role of COX-2 implies again the modulation of angiogenesis either by augmenting the release of the angiogenic peptide VEGF by tumor cells or by directly increasing the production of PGs. COX-2 may have an influence in the control of cell cycle regulation by inhibiting cyclin-dependent kinase inhibitor 1B (p27 (KIP1)), a negative regulator of cell cycle progression. COX-2 specific inhibitor enhances p27 (KIP1) expression via post-translational regulation and induced G1 growth arrest in COX-2-overexpressing cancer cells [42]. High expression of p27 (KIP1) is a favorable independent prognostic parameter for breast cancer [43]. MAPK signaling remains one of the important regulators of the cell cycle through its relation to COX-2 expression and also through other COX2-independent pathways (regulating PEA3), which seem to be predominant [44]. Further studies are needed to find the possible role of COX-2 on p27 (KIP1) in breast cancer. COX-2 also controls the extra cellular environment by inhibiting the level of E-cadherin in colon cancer cell [45]. E-cadherin is a hemophilic cell adhesion molecule and its expression is well preserved in normal breast tissue. Com-
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Fig. 1. Induction and regulation of angiogenic factors in breast cancer. The established causative factors activate COX-2, VEGF, and other tumor inducing factors through different signaling pathway. ER, estrogen receptor; IGF, insulin like growth factor; TGF, transforming growth factor; HIF, hypoxia inducible factor; PKB, phosphokinase B; TNF, tumor necrosing factor; VEGF, vascular endothelial growth factor; COX, cyclooxigenase; NF-jB, nuclear factor kappa B.
Role of hypoxia in angiogenesis Hypoxia
Arachidonic acid COX-2 HIF-1 α +Arnt PGE2
HIF-1 Transcription
VEGF
Fig. 2. Effect of hypoxia in angiogenesis. Hypoxia up-regulates COX-2, which increases the conversion of PGE2 from arachidonic acid. PGE2 then induce entry of HIF-1a from cytosol into the nucleus. In the nucleus HIF-1a binds with Arnt/HIF-1a and induce transcription of VEGF as well as other angiogenic factors. PGE, prostaglandin E; Arnt, aromatic hydrocarbon nuclear translocator.
pared with expression in non-tumorous tissues, E-cadherin is under expression in most breast cancer tissues [46]. The controlling function of COX-2 on E-cadherin expression can affect the metastatic and invasive potential of breast cancer cells as this molecule has been recognized as a key-factor in these cancer cell features. All of the relationships above can directly connect tumor progression with already well-recognized COX-2-promoting factors. This identification provides double beneficial results, suggesting that COX-2 may be an important regulatory link between tumor progression and already known tumorigenic factors. 4. Therapeutic role of angiogenic inhibitors in cancer Masferrer et al. [47] classified COX-2 inhibitors as a new class of anti-angiogenic agent. Because several studies suggest that tumor derived growth factors promote angiogenesis by inducing the production of COX-2 derived PGE2 and, COX-2 specific inhibitors consistently and effectively inhibited tumor growth and angiogenesis. COX-2 has been impli-
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cated in the carcinogenic process of several human tumors and furthermore its up regulation becomes an independent index of prognosis among cancer patients. Recent clinical studies have indicated that the presence of COX-2 in human lung and colon cancers is associated with poor prognosis [48,49]. Subsequently, COX-2 inhibition has become a field of special interest concerning tumor development prevention and regression. Non-steroidal anti-inflammatory drugs (NSAIDs) can down regulate COX-2 expression and demonstrate anticancer activity. At carcinogenesis, broad anti-carcinogenic effects of NSAIDs have been recognized both in vivo (laboratory animals) as well as in vitro (cell lines) models [50,51]. Additionally, several population-based studies have detected a 40–50% decrease in relative risk for colorectal cancer in persons who regularly use aspirin and other NSAIDs [52,53]. The beneficial results from NSAIDs use are well established even during the later stages of cancer progression, as there is many studies showing that NSAIDs can reduce both the size and number of experimentally induced tumors by inhibiting PG production. NSAIDs may also affect tumorigenesis through mechanisms other than the inhibition of PG synthesis [54]. Treatment with the selective COX-2 inhibitor (celecoxib, NS-398 and SC-58125) induces a marked reduction in the growth of a variety of neoplasms including colon [55], head and neck [56], skin [57] and bladder [58]. Furthermore, COX-2 specific inhibitors alter angiogenesis and tumor growth by inhibiting the expression of angiogenic factors and decrease the production of PGs [59]. More specifically, NS398 restores tumor cell apoptosis and reduces microvascular density and tumor growth of PC-3 prostate carcinoma cells xenografted into nude mice [60]. NS398 inhibits PGE2 synthesis and induces G1 growth arrest and/or apoptosis in human lung cancer cells. Induction of apoptosis of high COX-2-expressing lung cancer cells by NS398 is observed in cells cultured under serum-free condition. However, the same drug induces G1 growth arrest rather than apoptosis when maintained in 10% serum medium. These results suggest that the cytotoxic effect of COX-2 inhibitors on cancer cells may be influenced by extracellular environments [61]. SC-58125, causes growth inhibition of human colon carcinoma cell line in nude mice. The growth inhibitory effect of this specific COX-2-inhibitor seems to be mediated through cell cycle arrest because SC-58125 inhibits the p34 (cdc2) protein level and activity [62]. Further studies with selective COX-2 inhibitors are required to define at a molecular level of this mechanism in breast cancer. Obviously, a new approach for the prevention of breast cancer could be of merit for cancer patients. Recently, Abiru et al. [63] have shown that both aspirin and NS-398 effectively suppress NF-jB activity in hepatoma cells. On the other hand, Callejas et al. [64] have shown an absence of NF-jB inhibition by NSAIDs in hepatocytes and these findings differ from other cancers, such as colon cancer.
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Therefore, additional studies are warranted to find out the exact mechanism of NSAIDs in breast cancer. 5. COX-2 inhibitor as an anti-angiogenic agent It is clear that COX-2 is involved in carcinogenesis and tumor progression and its inhibition results in tumor suppression. At present, data on the activity of NSAIDs and selective COX-2 inhibitors in patients with breast cancer is limited. Additionally, recent data indicates that COX-2 inhibitors are powerful anti-angiogenic agents in vivo. Thus, there might be an adjuvant role for COX-2 inhibitors in the treatment of tumors as well as a primary role in cancer. Considerable progress has been made in understanding the relationship between COX-2 and tumorigenesis in many cancers; however, numerous questions still remain unanswered in breast cancer. It is now well established that breast cancer growth is angiogenesis dependent where VEGF and PGs play central roles. Therefore, further studies are important in the clarification of the angiogenic effects of COX-2 in breast cancer cells. NSAIDs also target hormone receptors to inhibit prostate carcinoma cell growth and are thus potential candidates for the chemoprevention of human prostate cancer by modulating hormone receptor [65]. Estrogen and its receptor play an important role in breast carcinogenesis both in animals and humans. It has been shown that, anti-estrogens may have a suppressive effect on breast-carcinogenesis [66]. It is also necessary to elucidate the relationship between ER and COX-2 status in breast cancer. Breast cancer is thought to be a genetic disorder; abnormalities of pro- and anti-apoptotic genes (BRCA) have been reported during its initiation and progression [67]. Mutations of these genes might be associated with the induction of COX-2 expression. Recently, it has been suggested that both COX-2 specific and non-specific inhibitors can increase the level of prostate apoptosis response 4 (Par-4), a pro-apoptotic gene in colorectal carcinoma prior to apoptosis [68]. Similar mechanisms of NSAID action may also work in breast cancer. Future studies are needed to understand the exact relationship between gene mutations and status of COX-2 levels in breast cancer. COX-2 behaves as an IE response gene and is subject to rapid regulation at the transcriptional level. Increased activity of COX-2 is thought to produce excessive amounts of PGs. PGs contribute to tumor growth by inducing the formation of new blood vessels that sustain tumor cell viability and growth. Furthermore, the local immunosuppressive function of COX-2 overexpression has been characterized as an important component in cancer progression [69] and has been specifically described in colon cancer [70]. Overall, COX-2 seems to have a significant therapeutic potential against carcinoma and results of recent studies suggest the possibility for the chemoprevention of breast cancer by the new generations of anti-COX-2 therapy. Recently, additional anti-inflammatory mechanism of selective cyclooxygenase-2 inhibitors has been reported [71]. How-
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ever, before recommending these drugs as routine prophylaxis, further clinical studies regarding the safety profile of these drugs and identification of cohorts at high risk for subsequent development of breast cancer should be conducted. 6. Conclusion For clinical applications of tumor angiogenesis, various approaches have been widely considered. Change of angiogenesis phenotype in tumors might be useful for the imaging and diagnosis of early stage minimal breast cancer. Therefore, anti-angiogenesis might be a new strategy for antitumor therapy. Some clinical trials assessing the anti-tumor activity of the angiogenesis inhibitors are going on. It is important to emphasize that no single angiogenic factor is found in all tumors, and angiogenesis may be triggered by different pathways in different tumors. Among the factors, VEGF also referred to as VPF has been characterized as the most potent regulator of angiogenesis in human carcinogenesis. FGF, especially the bFGF are one of the bestcharacterized and most potent angiogenic factors. Recently, another tyrosin kinase receptor family, TIE-1 and TIE-2 receptors, have been found to be critically involved in angiogenesis. VHL tumor suppressor gene product has been found to play a critical role in the activation of HIF-1, which might lead to a new understanding of the mechanism of hypoxiainduced neovascularization. Tumor growth and metastasis are angiogenesisdependent. The possibility of inhibiting tumor growth by interfering with the formation of new vessels has recently raised considerable interest. Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. Endostatin and angiostatin are known as angiogenesis inhibitors, inhibits endothelial cell proliferation and suppresses tumor growth and metastases. Several recent reports have questioned the efficacy of endostatin as a tumor suppressor in experimental animals. However, recently it has been suggested that their effects may be mediated, partially, by down-regulation of VEGF expression within the tumor [72]. In another study, it has been reported that endostatin treatment did not reduce the number of preinvasive lesions, proliferation rates or apoptotic index, compared with controls but, mRNA levels of a variety of proangiogenic factors (VEGF, VEGF receptors Flk-1 and Flt-1, angiopoietin-2, Tie-1, cadherin-5 and PECAM) were significantly decreased during mammary gland adenocarcinoma tumor progression in the C3 (1)/Tag transgenic model [73]. Breast tumor growth and metastasization are both hormone-sensitive and angiogenesis-dependent. A single angiogenic inhibitor is not capable to inhibit angiogenesis. Therefore, we need a balanced combination of angiogenesis inhibitors. At present, anti-angiogenesis therapies require long-term and continuous administration of the agents. Their use is appropriate in the earlier stages of disease, especially for improving survival in patients with a poor prognosis if
toxic effects can be made tolerable. Looking at the future, multidisciplinary approaches involving anti-angiogenic strategies should improve patients’ prognosis and their quality of life.
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Dossier: Breast cancers
Anti-angiogenic therapy in breast cancer Mohammad Atiqur Rahman, Masakazu Toi * Breast Cancer Research Program, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan Received 10 September 2003
Abstract Breast cancer is a worldwide epidemic among women, and one of the most rapidly increasing cancers. Not only the incidence rate but also the death rate is increasing. Despite enthusiastic efforts in early diagnosis, aggressive surgical treatment and application of additional non-operative modalities, its prognosis is still dismal. This emphasizes the necessity to develop new measures and strategies for its prevention. The understanding of the biology of angiogenesis is improving rapidly, offering the hope for more specific vascular targeting of tumor neovasculature. Anti-angiogenic therapy is a promising, relatively new form of cancer treatment using drugs called angiogenesis inhibitors that specifically inhibit new blood vessel growth. Extensive studies conducted over the past few years have recognized that overexpression of COX-2, VEGF in the cancer might be the leading factors, can induce angiogenesis via induction of multiple pro-angiogenic regulators. Breast tumor growth and metastasization are both hormone-sensitive and angiogenesis-dependent. A single angiogenic inhibitor is not capable to inhibit angiogenesis. Therefore, we should select a combination of angiogenesis inhibitors targeting COX-2, VEGF, and bFGF pathway. This article reviews the background and implementation of the current use of angiogenesis inhibitors and discusses the likely therapeutic roles in the early and advanced breast cancer together with its potential for chemoprevention. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: COX-2; VEGF; Breast cancer; Angiogenesis; Cancer prevention
1. Introduction Angiogenesis, formation of new capillaries from preexisting blood vessels, not only is important in physiological processes but also contributes in a variety of pathological processes, and various inflammatory disorders [1]. In particular, for the localization and expansion of a small solid tumor into neoplasm, angiogenesis is the vital process, and making cancer a clinically relevant target for antiangiogenesis therapy [2]. Tumor angiogenesis is a complex mechanism consisting of multi-step events including secretion or activation of angiogenic factors by tumor cells, activation of proteolytic enzymes, and proliferation, migration, and differentiation of endothelial cells [3]. Anti-angiogenic therapy represents a new promising therapeutic modality in solid tumors. It may also be used as a maintenance therapy to prevent the metastasis or recurrence. Current approaches to target angiogenesis rely on inhibiting growth factors that stimulate vascular endothelial cells or blocking their receptors to breast cancer. * Corresponding author. E-mail address: [email protected] (M. Toi). © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. doi:10.1016/j.biopha.2003.09.009
Breast cancer is the most common primary cancer with poor prognosis. Although localized breast cancer can be cured by surgery, breast cancer has a high mortality rate primarily due to frequent metastasis while the primary tumor is undetected. Breast cancer development is a complex process associated with an accumulation of genetic and epigenetic changes that run through the steps of initiation, promotion and progression. However, the precise implication of etiological factors in the genetic pathway of breast cancer development has not yet been fully understood. Accordingly, understanding the mechanisms that control breast cancer growth behavior is of great importance in order to prevent and more efficiently control its genesis. Beyond any doubt this fundamental understanding of tumor biological and molecular behavior can be proved to be of high validity in the evolution of effective therapy. Cyclooxygenase (COX), constitutively expressed COX-1 and inducible COX-2, which has recently been categorized as an immediate-early (IE) response gene, are the rate-limiting enzymes catalyzing the production of prostanoids (prostaglandins (PGs) and thromboxanes) from arachidonic acid. As COX-2 expression is minimal in different, normal and human tissues, COX-2
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overexpression in cancer tissues has been implicated as a promoting factor in carcinogenesis, whilst genetic deletion or pharmacological inhibition of COX-2 suppresses tumorigenesis [4,5]. Additionally, the localization of factors (NFjB, selective promoter factor (SP-1), CCAAT enhancerbinding proteins) well connected with breast cancer progression in the promoter region of COX-2 [6] emphasizes the central role that COX-2 can play in breast cancer biology. 2. Natural history of angiogenesis in breast cancer Both primary and metastasis tumors in the breast are dependent on angiogenesis and primary malignant breast tumors are among those human neoplasms that exhibit the greatest angiogenic activity. Recently, the significance of tumor angiogenesis as a prognostic indicator has been documented in various kinds of human tumors [7,8]. The development of immunohistochemical techniques using monoclonal antibodies against endothelial mitogens like factor VIII-related antigen (RA) allowed the semiquantitative analysis of microvessel proliferation in tumor tissues [9]. Using this evaluation method, Weidner et al. [10] first reported that tumor angiogenesis is an independent prognostic indicator in primary breast cancer. Furthermore, Hork et al. [11] confirmed its value by an immunocytochemical method using another monoclonal antibody for platelet/endothelial cell adhesion molecule, CD-31. We also found that microvessel density (MVD) is a potent prognostic indicator in primary breast cancer [12]. Recently, Costa et al. [13] showed a significant correlation between COX-2 expression and MVD in human breast cancer. COX-2 can be induced by a variety of factors including tumor promoters, cytokines, growth factors and hypoxia. Recent findings have demonstrated that activation of the mitogenic-activated protein kinase (MAPK) and protein kinase B signaling pathways (Akt/PKB signaling pathways) are important in both the transcriptional and posttranscriptional regulation of COX-2 expression [14]. HuR protein, an ubiquitously expressed member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, has been identified as a trans-acting factor involved in mRNA-stabilization and has been characterized as an important mRNA-stability factor [15]. Recent studies suggest that HuR, by binding to the COX-2 AU-rich element prolongs the half-life of COX-2 mRNA and ultimately leads to the overexpression of COX-2 in colon carcinoma cells [16]. A similar mechanism responsible for the COX-2 overexpression in breast cancer cells may also occur, as a high expression of HuR has been observed in breast cancer cell lines [17]. Thus, future studies investigating the relationship between HuR and COX-2 in breast cancer would be of special interest. Vascular endothelial growth factors (VEGF) also referred to as vascular permeability factor (VPF) has been characterized as the most potent regulator of angiogenesis in human carcinogenesis. VEGF exerts its biologic activities through two transmembrane tyrosine kinase receptors: the fms-like
tyrosine kinase receptor (Flt-1, or VEGFR1) and kinase insert domain-containing receptor (KDR or VEGFR2). Recent results suggest that human anti-KDR antibodies may have potential application in the treatment of cancer and other diseases in which pathologic angiogenesis occurs [18]. In a recent study, it has been shown that an oral DNA vaccine that selectively targets VEGFR2 is capable of preventing effective angiogenesis and inhibits tumor growth [19], which demonstrated that immunotherapy directed against proliferating endothelial cells could be used to selectively target malignancy [20]. Various therapeutic approaches aimed at inhibiting the function of VEGF are currently under investigation [21]. VEGF-targeting treatments include large molecules such as neutralizing antibodies against VEGF, VEGFRs, the soluble form of VEGFR1 (sVEGFR1), and small molecules such as signal transduction inhibitors. sVEGFR1, an intrinsic inhibitor of VEGF, frequently co-expressed with VEGF in primary breast cancer tissues. The balance between sVEGFR1 and VEGF levels in breast cancer tissues provided more statistically significant prognostic value than VEGF alone, supported an anti-angiogenesis treatment including anti-VEGF therapy [22]. Recombinant humanized monoclonal antibodies to VEGF (rhuMab VEGF) are now being investigated in phase II/III clinical trials. Results from phase I study show that rhuMab VEGF was well tolerated in various doses, and pharmacokinetic studies indicated that the antibody had a similar half-life to other humanized antibodies. According to a recent presentation at 2003 American Society of Clinical Oncology (ASCO) meeting, it was documented that an addition of rhuMab VEGF to conventional standard treatment improved the survival outcomes in colo-rectal cancer magnificently. In metastatic breast cancer, it was also shown that rhuMab VEGF plus capecitabine achieved a significantly higher tumor response rate as compared with capecitabine alone in the third-line treatment, despite the survival advantage not being demonstrated. Experimentally, monoclonal antibodies against VEGFR1 and VEGFR2 have activities against various types of tumors [23]. In a neuroblastoma model, combination therapy with a monoclonal neutralizing antibody targeting VEGFR2 and vinblastine resulted in full and sustained regression of large established tumors, without an increase in toxic effects or any signs of acquired drug resistance during the treatment period [24]; this approach, therefore, seems promising. Treatment with the soluble form of VEGFR1 has also shown to inhibit VEGF-induced neovascularization, because soluble VEGFR1 can bind to VEGF with high affinity and neutralize its activity effectively. Recently, a new form of VEGF receptor, neuropilin-1, has been identified, which plays an important role in vasculogenesis [25] and is involved in VEGF mediated angiogenesis in vivo [26,27]. Matthies et al. [28] showed that anti-neuropilin exhibited a significant decrease in wound angiogenesis. However, additional studies are needed to explain the mechanism of neuropilin-1 activity in angiogenesis.
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Platelet derived growth factor (PDGF) and its receptor (PDGFR) transduce signals that direct cellular growth, division, and migration. Increased PDGF/PDGFR activity is required for angiogenesis and may be oncogenic. Receptor binding by PDGF is known to activate intracellular tyrosine kinase, leading to autophosphorylation of the cytoplasmic domain of the receptor as well as phosphorylation of other intracellular substrates. PDGF has been identified as a potential autocrine growth factor for sarcoma [29]. Breast carcinomas are known to express PDGF [30]. Recently, it has been shown that Gleevec (tyrosin kinase inhibitor) can exert its inhibitory effect on tumor cells through inhibiting PDGF receptor function in primary non-small cell lung cancer [31]. Gleevec, that has been proven to be effective for clinical cancer patients, represents a new direction in drug design targeting specific tyrosine kinases important for intracellular signal transduction pathway. Fibroblast growth factors (FGF), especially the bFGF are one of the best-characterized and most potent angiogenic factors. Recently, another tyrosin kinase receptor family, TIE-1 and TIE-2 receptors, have been found to be critically involved in angiogenesis. Von Hippel– Lindau (VHL) tumor suppressor gene product has been found to play a critical role in the activation of hypoxia inducible factor-1 alpha (HIF-1a), which might lead to a new understanding for the mechanism of hypoxia-induced neovascularization. Her-2/new may regulate COX-2 production of proinflammatory PGs, both in the ER positive and negative breast cancer, which is known to play a key role in tumor development. Further research is necessary to elucidate the roles of Her-2/new and COX-2 in the development of breast cancer. Angiogenesis is a multistep cascade involving various soluble mediators, and interacts closely with the immune system either directly or indirectly. Particularly, macrophage chemoattractant protein-1 (MCP-1), an important angiogenic factor [32], has been shown to correlate significantly with angiogenesis and TAM accumulation in primary breast cancer [33]. Furthermore, a combined MCP-1 and VEGF status was an independent prognostic indicator, which suggests that the immune-regulating function and angiogenic function of MCP-1 might contribute to the poor prognosis of breast cancer [33]. On the other hand, thymidine phosphorylase (TP) an important angiogenic enzymes, induce new blood vessel formation in many human malignancies. TPoverexpressing tumor cells grow faster and form more angiogenic tumors than do wild-type TP (–) ve tumor cells in nude mice. TP expression was positively associated with MVD and with poor prognosis in gastrointestinal cancer. In an immunohistochemical analysis, we also found that monocytic TP (+) ve breast tumors had a significantly worse prognosis than did monocytic TP (–) ve breast tumors [34]. Although there is no direct evidence of TP as an effective contributor to the angiogenic process, but it is associated with aggressive histological features when co-expressed with VEGF [35]. Recently, it has also been suggested that COX-2 expression was associated with TP expression.
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3. Regulation of angiogenic factor in breast cancer The concept of angiogenic factor was postulated by Folkman’s group two decades ago. In recent years, many new angiogenic factors have been identified and characterized, but still little is known about the relationship between specificity of angiogenic factors and type of tumor. With the emergence of anti-angiogenic therapy as a novel anti-cancer treatment, the value of understanding the mechanism(s) driving the regulation of angiogenic mediators, such as VEGF in breast cancer, has increased. Often produced at high levels by tumor cells, VEGF is a well-known mediator of tumor angiogenesis, which stimulates EC growth and enhances vascular permeability. According to several hypotheses, in human breast cancers COX-2 overexpression is linked to VEGF overexpression and, therefore, tumor angiogenesis [36] and/or PG production (Fig. 1). The hypoxia-induced VEGF up regulation can be mediated by COX-2 [37]. In hypoxic condition, overexpression of COX-2 induces VEGF expression by modulating HIF-1a [38]. It has been shown that PGE2 induce translocation of HIF-1 alpha into the nucleus where it binds with ARNT/HIF-1a and then induce VEGF (Fig. 2). Furthermore, it is well known that PGs can induce tumor angiogenesis in an autocrine and/or paracrine fashion and even more specifically are important growth regulators as they stimulate cellular proliferation in rat and human (e.g. PGE2 and PGE2a) [39]. Although there are only a limited number of studies describing the role of COX-2 in angiogenesis and tumor neovascularization in breast cancer in particular, it seems that it is only a matter of time before the critical role of COX-2 in this high-importance mechanism for tumor growth is established [40]. Tumor vascularity is a strong indicator of its biological aggressiveness in breast cancer especially, as it is significantly correlated with clinical and histological grades of the carcinoma [41]. The protagonistic role of COX-2 implies again the modulation of angiogenesis either by augmenting the release of the angiogenic peptide VEGF by tumor cells or by directly increasing the production of PGs. COX-2 may have an influence in the control of cell cycle regulation by inhibiting cyclin-dependent kinase inhibitor 1B (p27 (KIP1)), a negative regulator of cell cycle progression. COX-2 specific inhibitor enhances p27 (KIP1) expression via post-translational regulation and induced G1 growth arrest in COX-2-overexpressing cancer cells [42]. High expression of p27 (KIP1) is a favorable independent prognostic parameter for breast cancer [43]. MAPK signaling remains one of the important regulators of the cell cycle through its relation to COX-2 expression and also through other COX2-independent pathways (regulating PEA3), which seem to be predominant [44]. Further studies are needed to find the possible role of COX-2 on p27 (KIP1) in breast cancer. COX-2 also controls the extra cellular environment by inhibiting the level of E-cadherin in colon cancer cell [45]. E-cadherin is a hemophilic cell adhesion molecule and its expression is well preserved in normal breast tissue. Com-
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Fig. 1. Induction and regulation of angiogenic factors in breast cancer. The established causative factors activate COX-2, VEGF, and other tumor inducing factors through different signaling pathway. ER, estrogen receptor; IGF, insulin like growth factor; TGF, transforming growth factor; HIF, hypoxia inducible factor; PKB, phosphokinase B; TNF, tumor necrosing factor; VEGF, vascular endothelial growth factor; COX, cyclooxigenase; NF-jB, nuclear factor kappa B.
Role of hypoxia in angiogenesis Hypoxia
Arachidonic acid COX-2 HIF-1 α +Arnt PGE2
HIF-1 Transcription
VEGF
Fig. 2. Effect of hypoxia in angiogenesis. Hypoxia up-regulates COX-2, which increases the conversion of PGE2 from arachidonic acid. PGE2 then induce entry of HIF-1a from cytosol into the nucleus. In the nucleus HIF-1a binds with Arnt/HIF-1a and induce transcription of VEGF as well as other angiogenic factors. PGE, prostaglandin E; Arnt, aromatic hydrocarbon nuclear translocator.
pared with expression in non-tumorous tissues, E-cadherin is under expression in most breast cancer tissues [46]. The controlling function of COX-2 on E-cadherin expression can affect the metastatic and invasive potential of breast cancer cells as this molecule has been recognized as a key-factor in these cancer cell features. All of the relationships above can directly connect tumor progression with already well-recognized COX-2-promoting factors. This identification provides double beneficial results, suggesting that COX-2 may be an important regulatory link between tumor progression and already known tumorigenic factors. 4. Therapeutic role of angiogenic inhibitors in cancer Masferrer et al. [47] classified COX-2 inhibitors as a new class of anti-angiogenic agent. Because several studies suggest that tumor derived growth factors promote angiogenesis by inducing the production of COX-2 derived PGE2 and, COX-2 specific inhibitors consistently and effectively inhibited tumor growth and angiogenesis. COX-2 has been impli-
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cated in the carcinogenic process of several human tumors and furthermore its up regulation becomes an independent index of prognosis among cancer patients. Recent clinical studies have indicated that the presence of COX-2 in human lung and colon cancers is associated with poor prognosis [48,49]. Subsequently, COX-2 inhibition has become a field of special interest concerning tumor development prevention and regression. Non-steroidal anti-inflammatory drugs (NSAIDs) can down regulate COX-2 expression and demonstrate anticancer activity. At carcinogenesis, broad anti-carcinogenic effects of NSAIDs have been recognized both in vivo (laboratory animals) as well as in vitro (cell lines) models [50,51]. Additionally, several population-based studies have detected a 40–50% decrease in relative risk for colorectal cancer in persons who regularly use aspirin and other NSAIDs [52,53]. The beneficial results from NSAIDs use are well established even during the later stages of cancer progression, as there is many studies showing that NSAIDs can reduce both the size and number of experimentally induced tumors by inhibiting PG production. NSAIDs may also affect tumorigenesis through mechanisms other than the inhibition of PG synthesis [54]. Treatment with the selective COX-2 inhibitor (celecoxib, NS-398 and SC-58125) induces a marked reduction in the growth of a variety of neoplasms including colon [55], head and neck [56], skin [57] and bladder [58]. Furthermore, COX-2 specific inhibitors alter angiogenesis and tumor growth by inhibiting the expression of angiogenic factors and decrease the production of PGs [59]. More specifically, NS398 restores tumor cell apoptosis and reduces microvascular density and tumor growth of PC-3 prostate carcinoma cells xenografted into nude mice [60]. NS398 inhibits PGE2 synthesis and induces G1 growth arrest and/or apoptosis in human lung cancer cells. Induction of apoptosis of high COX-2-expressing lung cancer cells by NS398 is observed in cells cultured under serum-free condition. However, the same drug induces G1 growth arrest rather than apoptosis when maintained in 10% serum medium. These results suggest that the cytotoxic effect of COX-2 inhibitors on cancer cells may be influenced by extracellular environments [61]. SC-58125, causes growth inhibition of human colon carcinoma cell line in nude mice. The growth inhibitory effect of this specific COX-2-inhibitor seems to be mediated through cell cycle arrest because SC-58125 inhibits the p34 (cdc2) protein level and activity [62]. Further studies with selective COX-2 inhibitors are required to define at a molecular level of this mechanism in breast cancer. Obviously, a new approach for the prevention of breast cancer could be of merit for cancer patients. Recently, Abiru et al. [63] have shown that both aspirin and NS-398 effectively suppress NF-jB activity in hepatoma cells. On the other hand, Callejas et al. [64] have shown an absence of NF-jB inhibition by NSAIDs in hepatocytes and these findings differ from other cancers, such as colon cancer.
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Therefore, additional studies are warranted to find out the exact mechanism of NSAIDs in breast cancer. 5. COX-2 inhibitor as an anti-angiogenic agent It is clear that COX-2 is involved in carcinogenesis and tumor progression and its inhibition results in tumor suppression. At present, data on the activity of NSAIDs and selective COX-2 inhibitors in patients with breast cancer is limited. Additionally, recent data indicates that COX-2 inhibitors are powerful anti-angiogenic agents in vivo. Thus, there might be an adjuvant role for COX-2 inhibitors in the treatment of tumors as well as a primary role in cancer. Considerable progress has been made in understanding the relationship between COX-2 and tumorigenesis in many cancers; however, numerous questions still remain unanswered in breast cancer. It is now well established that breast cancer growth is angiogenesis dependent where VEGF and PGs play central roles. Therefore, further studies are important in the clarification of the angiogenic effects of COX-2 in breast cancer cells. NSAIDs also target hormone receptors to inhibit prostate carcinoma cell growth and are thus potential candidates for the chemoprevention of human prostate cancer by modulating hormone receptor [65]. Estrogen and its receptor play an important role in breast carcinogenesis both in animals and humans. It has been shown that, anti-estrogens may have a suppressive effect on breast-carcinogenesis [66]. It is also necessary to elucidate the relationship between ER and COX-2 status in breast cancer. Breast cancer is thought to be a genetic disorder; abnormalities of pro- and anti-apoptotic genes (BRCA) have been reported during its initiation and progression [67]. Mutations of these genes might be associated with the induction of COX-2 expression. Recently, it has been suggested that both COX-2 specific and non-specific inhibitors can increase the level of prostate apoptosis response 4 (Par-4), a pro-apoptotic gene in colorectal carcinoma prior to apoptosis [68]. Similar mechanisms of NSAID action may also work in breast cancer. Future studies are needed to understand the exact relationship between gene mutations and status of COX-2 levels in breast cancer. COX-2 behaves as an IE response gene and is subject to rapid regulation at the transcriptional level. Increased activity of COX-2 is thought to produce excessive amounts of PGs. PGs contribute to tumor growth by inducing the formation of new blood vessels that sustain tumor cell viability and growth. Furthermore, the local immunosuppressive function of COX-2 overexpression has been characterized as an important component in cancer progression [69] and has been specifically described in colon cancer [70]. Overall, COX-2 seems to have a significant therapeutic potential against carcinoma and results of recent studies suggest the possibility for the chemoprevention of breast cancer by the new generations of anti-COX-2 therapy. Recently, additional anti-inflammatory mechanism of selective cyclooxygenase-2 inhibitors has been reported [71]. How-
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ever, before recommending these drugs as routine prophylaxis, further clinical studies regarding the safety profile of these drugs and identification of cohorts at high risk for subsequent development of breast cancer should be conducted. 6. Conclusion For clinical applications of tumor angiogenesis, various approaches have been widely considered. Change of angiogenesis phenotype in tumors might be useful for the imaging and diagnosis of early stage minimal breast cancer. Therefore, anti-angiogenesis might be a new strategy for antitumor therapy. Some clinical trials assessing the anti-tumor activity of the angiogenesis inhibitors are going on. It is important to emphasize that no single angiogenic factor is found in all tumors, and angiogenesis may be triggered by different pathways in different tumors. Among the factors, VEGF also referred to as VPF has been characterized as the most potent regulator of angiogenesis in human carcinogenesis. FGF, especially the bFGF are one of the bestcharacterized and most potent angiogenic factors. Recently, another tyrosin kinase receptor family, TIE-1 and TIE-2 receptors, have been found to be critically involved in angiogenesis. VHL tumor suppressor gene product has been found to play a critical role in the activation of HIF-1, which might lead to a new understanding of the mechanism of hypoxiainduced neovascularization. Tumor growth and metastasis are angiogenesisdependent. The possibility of inhibiting tumor growth by interfering with the formation of new vessels has recently raised considerable interest. Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. Endostatin and angiostatin are known as angiogenesis inhibitors, inhibits endothelial cell proliferation and suppresses tumor growth and metastases. Several recent reports have questioned the efficacy of endostatin as a tumor suppressor in experimental animals. However, recently it has been suggested that their effects may be mediated, partially, by down-regulation of VEGF expression within the tumor [72]. In another study, it has been reported that endostatin treatment did not reduce the number of preinvasive lesions, proliferation rates or apoptotic index, compared with controls but, mRNA levels of a variety of proangiogenic factors (VEGF, VEGF receptors Flk-1 and Flt-1, angiopoietin-2, Tie-1, cadherin-5 and PECAM) were significantly decreased during mammary gland adenocarcinoma tumor progression in the C3 (1)/Tag transgenic model [73]. Breast tumor growth and metastasization are both hormone-sensitive and angiogenesis-dependent. A single angiogenic inhibitor is not capable to inhibit angiogenesis. Therefore, we need a balanced combination of angiogenesis inhibitors. At present, anti-angiogenesis therapies require long-term and continuous administration of the agents. Their use is appropriate in the earlier stages of disease, especially for improving survival in patients with a poor prognosis if
toxic effects can be made tolerable. Looking at the future, multidisciplinary approaches involving anti-angiogenic strategies should improve patients’ prognosis and their quality of life.
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